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<p>Germinal centers (GCs) are specialized lymphoid structures in which activated B cells undergo clonal selection and B cell receptor (BCR) somatic hypermutation to generate high-affinity antibodies. Previous work has shown that T cells expressing choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), are linked to the production of high-affinity antibodies in the GC response. However, whether B cells in the GC also express ChAT, and the details of the interplay of cholinergic circuits within the GC, remain unclear. Here we show that <i>Chat</i> expressed by GC B cells contributes to the early accumulation of high-affinity GC B cells following antigen encounter. We identify key transcriptional regulators of <i>Chat</i> expression in GC B cells and demonstrate that ACh receptor (AChR) expression is dynamically coordinated during B cell activation. In vitro, we show that ACh binding to muscarinic AChRs limits plasma cell differentiation and dampens BCR signal transduction to fine-tune the threshold for affinity-based positive selection. Together, these findings reveal a previously unrecognized regulatory axis that operates early during GC selection and uses cholinergic signals to shape B cell fate decisions and humoral immunity.</p>

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Lymphocyte-derived cholinergic circuits modulate germinal center output and B cell activation

  • 期刊论文

  • 发表日期：

    2026年2月24日

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  • Duygu Nechanitzky,
  • Logan K. Smith,
  • Robert Nechanitzky,
  • Soode Moghadas Jafari,
  • Jillian Haight,
  • Christophe Bontoux,
  • Parameswaran Ramachandran,
  • Matthew J. Gold,
  • Andrew C. Wakeham,
  • Mary E. Saunders,
  • Justin F. Deniset,
  • Tak W. Mak

摘要

Germinal centers (GCs) are specialized lymphoid structures in which activated B cells undergo clonal selection and B cell receptor (BCR) somatic hypermutation to generate high-affinity antibodies. Previous work has shown that T cells expressing choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), are linked to the production of high-affinity antibodies in the GC response. However, whether B cells in the GC also express ChAT, and the details of the interplay of cholinergic circuits within the GC, remain unclear. Here we show that Chat expressed by GC B cells contributes to the early accumulation of high-affinity GC B cells following antigen encounter. We identify key transcriptional regulators of Chat expression in GC B cells and demonstrate that ACh receptor (AChR) expression is dynamically coordinated during B cell activation. In vitro, we show that ACh binding to muscarinic AChRs limits plasma cell differentiation and dampens BCR signal transduction to fine-tune the threshold for affinity-based positive selection. Together, these findings reveal a previously unrecognized regulatory axis that operates early during GC selection and uses cholinergic signals to shape B cell fate decisions and humoral immunity.